The overall UW ACE theme centers on a comprehensive development model of risk, risk processes, symptom emergence, and adaptation in autism spectrum disorder (ASD). According to this model, early autism risk factors (genetics, familial, and environmental) lead to risk processes, namely altered patterns of interaction between the child and his/her environment, which, in turn, contribute to the abnormal development of neural circuitry and atypical behavior. Project I has two major goals. First, it will identify autism susceptibility genes and their genomic location(s): genes in which variation affects risk for ASD. Second, it will seek to expand the set of component traits (endophenotypes) for which there is evidence for a genetic basis. Identification of susceptibility genes will lead to identification of underlying biological mechanisms, and offers the promise of presymptomatic diagnosis and, ultimately, of disease-modifying medications or other therapies for use early in disease and during the presymptomatic period. The specific aims of Project I build on our previous work funded by the NICHD CPEA program in which we recruited a large sample of multiplex nuclear autism families, genotyped the family members, and comprehensively evaluated them with multiple measures. In Project I we propose to extend this research program with the goal of identifying risk genes and chromosomal locations of risk genes that contribute to ASD endophenotypes. We will recruit additional adult relatives from our existing sample of families, and will collect phenotype and genotype data on these relatives. We will use these extended families and the remainder of our previously-collected nuclear families to identify genomic regions that contain ASD risk genes. Our approach will use these novel endophenotypes from all family members coupled with state-of-the art statistical genetic analyses. We will also investigate new phenotypes to extend the possible panel of endophenotypes by determining which of these measures in parents are associated with autism in their children. This,project directly addresses goals outlined in the NIH Autism Research Matrix, including (1) identification of biological risk indices for the development of autism and autism-related symptoms in infants, such as language and social impairments, and (2) identification of autism susceptibility genes.